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SAR110894, a potent histamine H3-receptor antagonist, displays disease-modifying activity in a transgenic mouse model
Philippe Delay-Goyet1, Véronique Blanchard1, Nathalie Schussler1
1Neurodegeneration and Pain Unit, Sanofi R&D, Chilly-Mazarin, France.
Introduction:
Tau hyperphosphorylation and neurofibrillary tangles are histopathologic hallmarks of tauopathies. Histamine H3-receptor antagonists have been proposed to reduce tau hyperphosphorylation in preclinical models.
Methods:
We evaluated the ability of SAR110894, a selective histamine H3-receptor antagonist, to inhibit tau pathology and prevent cognitive deficits in a tau transgenic mouse model (THY-Tau22).
Results:
SAR110894 treatment for 6 months (but not 2 weeks) in THY-Tau22 mice decreased both tau hyperphosphorylation at pSer396-pSer404 (AD2 signal) in the hippocampus and the number of AT8 (pSer199/202-Thr205) positive cells in the cortex and decreased the formation of neurofibrillary tangles in the cortex, hippocampus, and amygdala. Macrophage inflammatory protein 1-alpha messenger RNA expression was decreased in the hippocampus. SAR110894 also prevented episodic memory deficits, and this effect was still detected after treatment washout.
Discussion:
Long-term SAR110894 treatment could have potential disease modifying activity in neurodegenerative tauopathies.
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